Crigler-Najjar syndrome (CN) is an autosomal recessive disorder with severe unconjugated hyperbilirubinemia due to deficiency of bilirubin UDP-glucuronosyltransferase isozyme 1A1 (UGT1A1) encoded by the UGT1A1 gene (OMIM #218800). The prevalence of CN is about 1/1000000 individuals at birth, making CN an ultra-rare disease. Current therapy for CN relies on phototherapy to prevent elevations of serum bilirubin levels. For the mild form of the disease, also known as CN type II, phenobarbital can be used to lower bilirubinemia.
Nonetheless patients are potentially exposed to the risk of life-threatening spikes in bilirubin in blood and liver transplantation remains the only curative treatment. In its most severe form, the disease is lethal due to bilirubin-induced neurological damage unless phototherapy is applied from birth. Despite the availability of a therapy, CN remains an unmet medical need for a number of reasons including loss of efficacy of phototherapy during growth, poor compliance due to the limitation of phototherapy itself (which needs to be carried on for 10-12 hours each day), and occurrence of pathological liver changes over time, which may require liver transplantation.
Different animal models of the disease exist, including the naturally occurring Gunn rat and a more recent knock-in mouse model of the disease, developed by Dr. Muro at ICGEB in Trieste, Italy, which carries the same mutation present in the Gunn rat (Bortolussi et al., 2012). Gunn rats present high bilirubin levels in serum and they have cerebellar hyploplasia; CN mice have a much more severe phenotype, and die soon after birth if not promptly treated with phototherapy or gene therapy (Bortolussi et al., 2012).
Prior studies aimed at developing a gene-based therapy for CN showed that therapeutic efficacy could be achieved using AAV vectors delivered to the liver (Bortolussi et al., 2012; Seppen et al., 2006). However, a need for a more efficient therapeutic strategy still exists.
Gilbert's syndrome (or GS; OMIM #218800) is a genetic liver disorder and the most common hereditary cause of increased bilirubin. It is found in up to 3-12% of the population. GS is also caused by mutations in the UGT1A1 gene. Therapeutic strategies aiming at reducing hyperbilirubinemia would therefore also be advantageously implemented in the treatment of GS.